Science, published online 4 April 2013, doi:10.1126/science.1236062

Science, published online 4 April 2013, doi:10.1126/science.1234769

Somatic mutations in the active sites of isocitrate dehydrogenases (IDH), enzymes that interconvert isocitrate and α-ketoglutarate (αKG), confer new activity that results in the reduction of αKG to R-2-hydroxyglutarate (R-2HG). R-2HG inhibits αKG-dependent dioxygenases, including histone and DNA demethylases, altering the epigenetic state of cells and thereby promoting cancer cell proliferation. It would be desirable to identify compounds that block the activity of mutant IDH enzymes. Wang et al. and Rohle et al. now report AGI-6780 and AGI-5198, potent and selective inhibitors of R140Q IDH2 and R132H IDH1, respectively. Structural and biochemical studies revealed that AGI-6780 binds the IDH2 dimer interface and is an allosteric inhibitor. Both AGI-6780 and AGI-5198 reduced the amounts of R-2HG. AGI-6780 induced the differentiation of leukemic blasts derived from patients, and AGI-5198 blocked the growth of IDH1-mutant glioma cells in soft agar and xenograft mouse models. High doses of AGI-5198 promoted gene expression changes that were consistent with differentiation and reduced repressive histone marks on promoters of these genes. These new inhibitors can be applied in additional preclinical experiments to determine whether the inhibition of mutant IDH enzymes is a viable approach to treating various cancer types and whether these inhibitors are leads that can be used to generate anticancer drugs.